The present invention relates to a Tanacetum parthenium extract substantially free of xcex1-unsaturated xcex3-lactones. The invention addition preparation of the extract and to pharmaceutical and cosmetic compositions containing a Tanacetum parthenium extract which is substantially free of parthenolide.
Extracts of Tanacetum parthenium, a plant belonging to the family Asteracee/Composite, also known as Altamisa, Crisanthemum, Leucanthemum, Pyrethrum parthenium as well as under the common name xe2x80x9cfeverfewxe2x80x9d, have traditionally been used in the treatment of migraine, vertigo, arthritis, menstrual disorders, fever, toothache, stomach ache and insect bites. Extracts of Tanacetum parthenium contain various volatile oils having mono- and/or sesquiterpene components, flavonoids, tannins, and pyrethrin, as well as terpenoids of the family of sesquiterpene lactones, known as germacranolides, guaianolides, and eudesmanolides. These latter compounds are characterized by an xcex1-unsaturated xcex3-lactone structure and contain in particular the compounds known as parthenolide, 3-xcex2-hydroxy-parthenoide, costunolide, 3-xcex2-hydroxy-costunolide, artemorin, 8-xcex1-hydroxy-estafiatin and chrysanthemonin. The presence of these sesquiterpene lactones is considered necessary for the extracts to achieve pharmacological activity (J. Pharm. Pharmacol., 1992, 44:391-5).
Particular attention has been focused on parthenolide, which is thought to be the fundamental active ingredient of these extracts, but which is also responsible for allergic reactions which can sometimes occur following treatment with the extracts of Tanacetum parthenium (see, for example, Arch. Dermatol. Forsch., 1975, 251(3):235-44; Arch. Dermatol. Forsch., 1976, 255(2):111-21; Contact Dermatitis, 1988,38(4):207-8; Am. J Contact Dermatol., 1998-9 (1):49-50; Br. J Dermatol., 1995, 132(4):543-7). Extracts of Tanacetum parthenium containing parthenolide are disclosed in International Publication Nos. WO 92/11857, WO 94/06800, and WO 98/39018, European Patent Nos. EP 0 553 658 and EP 0 098 041, and British Patent No. GB 2,166,952.
In a first embodiment the invention is directed to a Tanacetum parthenium extract which is substantially free of xcex1-unsaturated xcex3-lactones. In a preferred embodiment, the content of xcex1-unsaturated xcex3-lactones is below 0.2 wt %. More preferably, the xcex1-unsaturated xcex3-lactones are present in an amount of no more than 0.1 wt %.
In a further embodiment the extract is substantially free of parthenolide. Preferably the parthenolide content is below 0.2 wt %, and more preferably below 0. I wt %.
In another embodiment, the invention is directed to a Tanacetum parthenium extract which is obtainable by a process comprising the steps of:
(a) extracting a quantity of plant material from an aerial portion of Tanacetum parthenium with a solvent selected from the group consisting of acetone, an alcohol and mixtures of acetone or an alcohol with water, to form a first extract;
(b) extracting the first extract with a hydrocarbon solvent to produce a second extract having a hydrocarbon phase and a non-hydrocarbon phase;
(c) evaporating the hydrocarbon phase from the second extract to form a first residue;
(d) extracting the non-hydrocarbon phase with a non-polar solvent to form a third extract;
(e) evaporating the non-polar solvent portion of the third extract to produce a second residue and redissolving the second residue in a water-alcoholic solution of acid;
(f) adding to the water-alcoholic solution a quantity of a strongly basic resin;
(g) eluting the resin with an alcohol solution and separating the eluate from the resin;
(h) treating the resin with an alcoholic or water-alcoholic solution of an acid;
(i) concentrating the alcoholic or water-alcoholic solution to form a third residue;
(j) extracting the third residue with a non-polar solvent to produce a fourth extract;
(k) evaporating the non-polar solvent from step (j) to form a fourth residue;
(1) combining the first and the fourth residues with the third extract to form a mixture;
(m) evaporating a liquid portion of the mixture to form a fifth residue; and
(n) at least partially drying the fifth residue.
Still further, the invention is directed to a pharmaceutical composition containing an extract as described herein in admixture with a pharmaceutically acceptable carrier.
The invention is additionally directed to a process for forming an extract of Tanacetum parthenium substantially free of xcex1-unsaturated xcex3-lactone which includes the method steps set forth above.